Infectious enteric diseases are major health problem throughout the world. This application seeks to establish the University of Maryland Enterics Research Investigational Network (ERIN) Cooperative Research Center (CRC) to investigate important clinical, pathogenesis, and host response Issues of enteric disease. The particular enteric pathogens that will be the focus of this CRC are Shigella spp. and diarrheagenic E. coli (DEC), which were implicated as the bacterial pathogens most frequently isolated from fatal cases of diarrheal disease in the Global Enteric Multicenter Study (GEMS). The GEMS is being conducted at 7 sites in Africa and South Asia and is the largest study ever conducted of diarrheal disease in children under the age of 5. Clinical specimens and bacterial isolates from GEMS as well as hypotheses arising from this study will be further examined using a variety of approaches including bacterial pathogenesis assays, intestinal physiology studies, fecal adaptive immunity and immunological markers, bacterial genomics, microbiomes, and human SNP analysis. Three multi-component and highly integrated projects are proposed. Project 1 will focus on the pathogenesis of DEC and Shigella infections. Genome sequences of enteropathogenic E. coli (EPEC) strains isolated from lethal cases of diarrhea, from non-lethal infections and from controls will be determined. Potential EPEC virulence factors implicated in the genomic analysis will be further characterized using a variety of assays and models to study pathogenesis. An enterotoxin originally discovered in Shigella but also present in DEC will be further characterized. In Project 2, different aspects of host response will be studied, including physiology studies of intestinal tissue infected with wild type and mutant Shigella and DEC strains, as well as the characterization of fecal immunoglobulin and cytokine levels in stool specimens from GEMS patients. Project 3 will investigate clinical aspects using clinical specimens from GEMS to determine patient SNPs in genes previously associated with susceptibility to diarrheal disease, bacterial interactions using microbiome and laboratory co-infection studies, and studies on the pangenomics of Shigella strains isolated from lethal and non-lethal disease.